SNP Shot: Genomic Insights

Alport syndrome is an inherited disorder primarily affecting the kidneys, hearing, and eyes.

A hallmark of Alport syndrome is the gradual decline of kidney function. Almost all individuals with the condition experience blood in the urine (hematuria), signaling kidney dysfunction. Many also develop protein in the urine (proteinuria). As kidney function worsens, it can lead to end-stage renal disease (ESRD), requiring dialysis or a kidney transplant.

Hearing loss, specifically sensorineural hearing loss caused by inner ear abnormalities, commonly develops in late childhood or early adolescence in those with Alport syndrome. Some individuals may also have eye abnormalities such as misshapen lenses (anterior lenticonus) and abnormal coloration of the retina. These eye problems rarely cause significant vision impairment.

Males with Alport syndrome tend to experience more severe symptoms, including significant hearing loss, eye abnormalities, and progressive kidney disease, compared to affected females.

Inheritance:

Alport syndrome can be inherited in different ways. The majority of cases, about 80%, are caused by mutations in the COL4A5 gene and follow an X-linked inheritance pattern. The COL4A5 gene is located on the X chromosome. In males (with one X chromosome), a single mutated copy of the COL4A5 gene is enough to cause kidney failure and other severe symptoms. In females (with two X chromosomes), a single mutated copy usually only causes hematuria, although some females experience more severe symptoms. A key feature of X-linked inheritance is that fathers cannot transmit X-linked traits to their sons.

Approximately 15% of Alport syndrome cases are due to mutations in both copies of either the COL4A3 or COL4A4 gene, following an autosomal recessive inheritance pattern. In these cases, each parent carries one copy of the mutated gene and are referred to as carriers. Some carriers are asymptomatic, while others develop a milder condition called thin basement membrane nephropathy, characterized by hematuria.

Around 5% of Alport syndrome cases are inherited in an autosomal dominant manner. Individuals with this form have one mutation in either the COL4A3 or COL4A4 gene in each cell. It is currently unclear why some individuals with a single mutation in the COL4A3 or COL4A4 gene develop autosomal dominant Alport syndrome, while others develop thin basement membrane nephropathy.